A pharmaceutical composition and process for administering non-steroidal drugs which are protected against injury to the gastrointestinal tract by a combination of certain H1 and H2 receptor blockers.
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8. A process for reducing the potential of aspirin or of a pharmaceutically acceptable salt of aspirin, to induce gastrointestinal injury in a subject which comprises administering to said subject, based on the weight of the subject,
(a) from about 10 mg to about 100 mg per kg per day of an nsaid selected from the group consisting of aspirin and pharmaceutically acceptable salts of aspirin; (b) from about 2.5 μg to about 500 mg per kg per day of an H1 receptor blocker selected from the group consisting of diphenydramine and pharmaceutically acceptable salts of diphenydramine; and (c) from about 10 μg to about 1 g per kg per day of an H2 receptor binder selected from the group consisting of cimetidine, ranitidine, famotidine, and pharmaceutically acceptable salts thereof.
1. A nsaid composition having reduced potential for nsaid induced gastrointestinal injury comprising
(a) an analgesic or antiinflammatory amount of a nsaid selected from the group consisting of aspirin and pharmaceutically acceptable salts of aspirin; and (b) a protective amount of: (i) an H1 receptor blocker selected from the group consisting of diphenhydramine and pharmaceutically acceptable salts of diphenhydramine; and (ii) an H2 receptor blocker selected from the group consisting of cimetidine, ranitidine, famotidine and pharmaceutically acceptable salts thereof; said nsaid being present in the composition in an amount of from about 10 mg to about 100 mg per kg per day, based on the weight of a subject to whom the composition is being administered; said H1 receptor blocker being present in the composition in an amount of from about 2.5 g to about 500 mg per kg per day, based on the weight of a subject to whom the composition is being administered; and said H2 receptor being present in the composition in an amount of from about 10 g to about 1 g per kg per day, based on the weight of a subject to whom the composition is being administered.
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This application is a continuation in part of Ser. No. 836,264, filed Mar. 4, 1986 and now abandoned.
This invention relates to non-steroidal anti-inflammatory drug (hereinafter referred to as NSAID) compositions containing protectants against NSAID-induced gastrointestinal injury and to processes for administering such composition. More particularly, it concerns compositions and processes of the aforesaid type that employ certain combinations of histamine receptor blockers as the protectants. The compositions of this invention are useful in treating conditions and symptoms that are classically treated by the administration of NSAIDs e.g. headache pain, pain and inflammation associated with arthritis and other systemic diseases, elevated body temperatures etc.
Aspirin and other NSAIDs have long been the most popular drugs for the management of pain, inflammation and fever. However, one of the drawbacks in their use is the gastrointestinal injury and/or bleeding that sometimes accompanies their administration to individuals. This becomes a problem where large and sustained doses of NSAIDs must be given to control the symptoms, as for example, in the case of the management of arthritis.
It has now been found that NSAID-induced gastrointestinal injury can be significantly reduced when a combination of histamine receptor blockers and particularly a combination of H1 and H2 receptor blockers are administered concurrently with the NSAID.
As pointed out in U.S. Pat. No. 4,996,571 H1 and H2 receptor blockers form two well-known classes of pharmacologically active drugs that serve as blocking agents for histamine at H1 and H2 histamine receptor sites, respectively. Histamine receptor sites have been differentiated on the basis of the classes of antihistamines that can serve to block these sites. The fact that a drug is identified as an antihistamine does not necessarily mean that it will be effective in blocking all the known histamine receptor sites but may in fact be selective so that it will act at one site e.g. H1 site but not at another e.g. H2 site.
It has been reported in prior art that H2 receptor blocking agents or antagonists protect against aspirin-induced lesions in certain laboratory animals. One such study is a report in Gastroenterology Vol. 88, No. 5 part 2. p. 1344. It has also been reported that cyproheptadine has been evaluated as a protectant against aspirin induced gastrointestinal injury (Indian J. Med. Res. 1980, 71, p. 926-32). Although the cyproheptadine may have some H1 -receptor antagonist properties, it does not act exclusively at the H1 receptor sites but rather acts predominantly at the serotonin receptor sites.
Aside from the above the present invention has further significant distinctions from the teachings in the Indian Journal. For one thing in this reference the aspirin and the cyproheptadine are not coadministered as would be the case in the present invention. Furthermore the treatment in this reference with cyproheptadine is reported as not modifying the gastric acidity. This is contrary to the observations made in connection with the present invention. Moreover, the cyproheptadine was administered by intraperitoneal injection prior to the intragastric administration of the aspirin. In contrast to this the compositions of the present invention lend themselves to oral administration at which time the NSAID and the combination H1 and H2 receptor blockers are coadministered.
As will be pointed out in more detail below it has been found that by employing certain combinations of H1 and H2 histamine receptor blockers as further defined herein that these two act synergistically in their protective effect against NSAID-induced gastrointestinal injury. This was an unexpected result and would not have been anticipated on the basis of the present state of the art.
A number of H1 and H2 receptor blockers are known in the prior art which are useful for the purposes of the present invention. However, not all of the H1 receptors blockers are equally effective in practicing this invention. Those that are useful should also exhibit anticholinergic properties.
By way of illustrating the H1 receptor blockers that may be employed herein mention may be made of the following: ethanolamines (e.g. diphenhydramine or its hydrochloride salt; carbinoxamine or its maleate salt); ethylenediamines (e.g. tripelennamine or its hydrochloride or citrate salts); alkylamines (e.g. chlorpheniramine or its maleate salt, brompheniramine or its maleate salt); piperazines (e.g. hydroxyzine or its hydrochloride or pamoate salts, cyclizine or its hydrochloride or lactate salts, etc. To exemplify the H2 receptor blockers that may be advantageously used in the practice of this invention the following are given: cimetidene, ranitidine, famotidine, etc.
Generally any combination of H1, and H2 receptor blockers as outlined above are useful for the purpose of this invention. Nevertheless certain combinations of H1 and H2 receptor blockers have been found to be particularly efficacious. Thus the combination of chlorpheniramine plus ranitidine, diphenhydramine plus ranitidine, chlorpheniramine plus cimetidine, and diphenhydramine plus cimetidine are the combinations of choice in the present invention.
The H1 and H2 receptors blockers may be used in the form of their bases or in the form of their pharmaceutically acceptable salts. When employed as salts these will usually be acid addition salts wherein the acid portion may be hydrochloric, maleic, ascorbic, citric, pamoic, lactic, tartaric, etc.
The NSAIDs form a well-known class of drugs that are antiinflammatory analgesics. These have the common property of inhibiting the formation of prostagladins which have a protective affect on the gastrointestinal mucosa. See Goodman and Gilman "The Pharmacological Basis for Therapeutics" 7th Edition, p. 678. It is because of this inhibiting effect that the oral administration of drugs of this class tend to result in gastrointestinal injury and/or bleeding and is at least part of the problem that the present invention seeks to reduce or eliminate.
A number of NSAIDs are known in the prior art to which the present invention has application. The most commonly known group are the salicylates of which aspirin is the prime example. A further group of NSAIDs that have utility in connection with the instant invention are the proprionic acid derivatives. Included in this group are ibuprofen, naproxen. A further group of NSAIDs, employable herein are the fenamates and compounds closely related to them structurally. These may be illustrated by such compounds as mefenamic acid, meclofenamate sodium, diclofenac and its sodium salt. Also belonging to the class NSAIDs with which the present invention is concerned are the indole derivatives (e.g. indomethacin); pyrrole alkanoic acid derivatives (e.g. tolmetin); pyrazalone derivatives (e.g. phenylbutazone); oxicams (e.g. piroxicam), etc.
It is contemplated that in the practice of the present invention the NSAID and the histamine receptor blockers will be administered concurrently in a convenient product form. The essential ingredients of such products will be the H1 and H2 receptor blockers and the NSAID. Over and above this these products may also contain other ingredients which will to a large extent depend upon the particular dosage form of the product, e.g. tablets, capsules, powders, suspensions etc.
The quantity of H receptor blocker that will be contained in the composition of this invention may vary somewhat. All that is required is that an effective amount be present so that the H1 receptor blocker can make its contribution as a protectant against NSAID induced gastrointestinal injury.
Similarly the quantity of H2 receptor blocker in the present composition may also vary, Again, all that is required is that amount employed be an effective quantity which will enable the H2 receptor blocker to play its part as protectant.
The NSAID will be contained in the composition of this invention at levels at which it is generally found in therapeutic NSAID compositions intended for oral administration. This will usually be a pharmaceutically acceptable analgesic/ anti-inflammatory dose.
The quantitative relationship of the NSAID and the H1 and H2 receptor blockers contained in the present products may be expressed on the basis of the daily average dose of the ingredient, e.g mg/kg. of body weight/day. In this case the average daily dose for the ingredients will have the values in the range set forth in the following table:
| ______________________________________ |
| Ingredient |
| General Range Preferred Range |
| ______________________________________ |
| NSAID about 10/mg/kg/day |
| about 15 mg/kg/day to |
| to about about 75 mg/kg/day |
| 100 mg/kg/day |
| H1 Receptor |
| about 2.5 ug/kg/day |
| about 100 ug/kg/day to |
| Blocker to about about 50 mg/kg/day |
| 500 mg/kg/day |
| H2 Receptor |
| about 10 ug/kg/day |
| about 0.010 mg/kg/day to |
| Blocker to about about 10 mg/kg/day |
| 1 g/kg/day |
| ______________________________________ |
The unit dosage forms for the present products will be formulated for convenient oral administration. Each such unit will generally contain from about 200 mg to about 600 mg of NSAID, from about 0.1 mg to about 70 mg of H1 receptor blocker and from 0.5 mg to about 350 mg of H2 receptor blocker. In formulating these products pharmaceutically acceptable doses of the aforesaid ingredients within the ranges set out above will be employed.
Depending upon the dosage form employed the products of this invention may also contain other adjuvants that may be useful in formulating or administering the particular dosage form. Thus, for example, when administered as a tablet the products of this invention may also contain lubricants, excipients, binding agents, disintegrating agents, flavoring agents, etc. In addition these products may also contain other pharmaceutically active ingredients such as: decongestants, analgesic adjuvants, antihistamines, expectorants, antitussives, diuretics, other analgesics, other anti-inflammatory agents, antipyretics, antirheumatics, anti-oxidants, vasodilators, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids and biological peptides.
The products of this invention may take a variety of forms. As indicated above they may assume the form of tablets. However, the NSAID and the H1 and H2 receptor blockers may also be in powdered or granular form contained in edible capsules such as gelatin capsules. The present products may also take the form of suspensions or solutions of the above ingredients in a suitable liquid medium or as powders packaged in suitable paper envelopes.
The following Examples are given to further illustrate the present invention. It is to be understood, however, that this invention is not limited thereto.
| ______________________________________ |
| Aspirin 325 mg |
| Ranitidine hydrochloride |
| 3.33 mg |
| Chlorpheniramine maleate |
| 3.33 mg |
| ______________________________________ |
The above ingredients are mixed in powdered or granular form and loaded into gelatin capsules.
| ______________________________________ |
| Aspirin 325 mg |
| Cimetidine hydrochloride |
| 16.67 mg |
| Chlorpheniramine maleate |
| 3.33 mg |
| ______________________________________ |
Prepared as described in Example 1.
| ______________________________________ |
| Aspirin 325 mg |
| Cimetidine hydrochloride |
| 3.33 mg |
| Diphenhyramine hydrochloride |
| 16.67 mg |
| ______________________________________ |
Prepared as described in Example 1.
The following experiments were carried out to test the effectiveness of the combination of H1 and H2 receptor blockers in protecting the stomach against NSAID-induced gastrointestinal injury and to compare any protection afforded by the individual H1 and H2 receptor blockers. In these studies the H1 and H2 receptor blockers are used in the form of the following acid salts: ranitidine HCl, diphenhydramine HCl, chloropheniramine maleate, cimetidine HCl. A standard dose of 975 mg of aspirin is administered orally to dogs along with, respectively, treatment (a) through (h) as indicated below. The stomach lining of the dogs are examined endoscopically and rated as to the degree of injury. The results are given in the table following the description of the methodology.
| ______________________________________ |
| chlor- |
| treat- |
| cimetidine |
| ranitidine |
| diphenhydramine |
| pheniramine |
| ment 50 mg 10 mg 50 mg 10 mg |
| ______________________________________ |
| a x |
| b x |
| c x |
| d x |
| e x x |
| f x x |
| g x x |
| ______________________________________ |
All test formulations are prepared on the day of the tests. The capsules are placed in the back of the dog's throat. A stomach catheter with attached funnel is positioned in the dog's stomach and 50 ml. of deionized water is administered.
Healthy adult beagle dogs of either sex are selected for testing. Dogs are housed individually in stainless steel cages with grid floors to allow excreta to pass through. Room temperature in the holding rooms and test laboratories is maintained between 65° F. and 85° F. and relative humidity between 30% and 80%. Room lights remain on from 6:00 AM to 4:00 PM.
Each dog is trained to stand in a stanchion with sling support and to accept a bit tied in its mouth. A gastroscope is then passed through the bit into the dog's stomach. This training requires ten days to two weeks in most dogs.
To determine whether a dog is suitable for test purposes, its stomach is examined for a normal mucosa, and its gastric responsiveness to NSAID is evaluated (as under Test procedure). An acceptable gastric irritation score in the antrum must be 5 or greater, 2 hours after dosage.
Food is withheld from test dogs for 24 hrs. before the test and during the test and water is allowed ad lib. The dogs are moved into a holding area away from the kennel. Fasted dogs of either sex are examined gastroscopically to ensure that their stomachs have normal healthy mucosal linings. The dogs are dosed orally with test formulations, which are flushed into their stomachs with 5 ml. of deionized water. They are then re-examined two and four hours later for gastric petechiae and signs of bleeding according to the following scale:
0=uniform, pale to dark pink mucosa
1=darker pink or blotchy mucosa
2=petechias and/or light red streaks
3=few small lesions
4=many or connected small lesions (striations)
5=few large lesions
6=many large lesions
7=massive hemorrhagic damage
Severity of injury for each treatment and at each time is calculated as the mean gastric irritation score.
In addition to the endoscopic observation of the gastric mucosa of each dog a qualitative description of gastric fluid is recorded and a pH measurement is made of the gastric fluid. All of these are done 2 hours after administration of the test product.
A base line is established by measuring the various parameters after the administration of 975 mg of aspirin by itself. The resting stomach has an irritation score of 0 and a pH of 5 to 5.5. Aspirin alone produces injury which scores at approximately 5.6 after 2 hours and the gastric pH at this time is about 3.1. After 4 hours these values are 4.0 for the irritation factor and the pH is about 4.7. This indicates that a certain amount of healing takes place between the 2nd and 4th hour after administration.
The results of these tests with respect to the two hour injury daa are summarized in the following table below:
| ______________________________________ |
| 2 Hr. Score |
| Test Composition Injury pH |
| ______________________________________ |
| aspirin (975 mg) 5.6 3.1 |
| aspirin (975 mg) + 3.5 5.3 |
| ranitidine HCl (10 mg) |
| aspirin (975 mg) + 4.0 4.4 |
| chlorpheniramine maleate (10 mg) |
| aspirin (975 mg) + 2.4 5.6 |
| cimetidine HCl (50 mg) |
| aspirin (975 mg) + 4.0 3.6 |
| diphenhydramine HCl (50 mg) |
| aspirin (975 mg) + 0.6 5.4 |
| ranitidine HCl (10 mg) + |
| diphenhydramine HCl (50 mg) |
| aspirin (975 mg) + ranitidine HCl |
| 1.6 4.7 |
| (10 mg) + chlorpheniramine maleate (10 mg) |
| aspirin (975 mg) + cimetidine HCl |
| 1.0 7.0 |
| (50 mg) + diphenhydramine HCl (50 mg) |
| ______________________________________ |
An examination of these data shows that singificantly more, synergistic protection is obtained when a combination of an H1 and H2 receptor blocker is employed together with aspirin as compared with the cases in which H1 or H2 receptor blocker, respectively, is issued alone.
Koslo, Randy J., Lukacsko, Alison B., Piala, Joseph J.
| Patent | Priority | Assignee | Title |
| 10603283, | Dec 28 2011 | GENUS LIFESCIENCES, INC | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
| 11324727, | Jul 15 2020 | Schabar Research Associates LLC | Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn |
| 11331307, | Jul 15 2020 | Schabar Research Associates LLC | Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn |
| 5037815, | Mar 04 1986 | BRISTOL-MYERS SQUIBB COMPANY, A CORP OF DE | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 - and H2 -receptor blockers |
| 5204118, | Nov 02 1989 | McNeil-PPC, Inc. | Pharmaceutical compositions and methods for treating the symptoms of overindulgence |
| 5260333, | Aug 11 1986 | Bristol Myers Squibb Company | Effect of a combination of a terbutaline, diphenhydramine and ranitidine composition on gastrointestinal injury produced by nonsteroidal anti-inflammatory compositions |
| 5352688, | Feb 15 1991 | The Mount Sinai School of Medicine of the City University of New York | Methods for the treatment of bradyphrenia in parkinson's disease |
| 5417980, | Nov 02 1989 | McNeil-PPC, Inc. | Pharmaceutical compositions and methods for treating the symptoms of overindulgence |
| 5453428, | Feb 14 1991 | The Mount Sinai School of Medicine of the City of New York | Method and composition for the treatment of apathy-amotivation syndrome |
| 5474985, | Dec 22 1993 | Regents of the University of California, The | Preventing and treating elevated intraocular pressure associated with administered or endogenous steroids using non-steroidal cyclooxygenase inhibitors |
| 5496836, | May 05 1994 | Mount Sinai School of Medicine of the City University of New York | Use of famotidine and related compounds in the treatment of movement disorders |
| 5547969, | Feb 14 1991 | Mount Sinai School of Medicine of the City University of New York | Method for the treatment of bradyphrenia in Parkinson's disease patients |
| 5599535, | Jun 07 1995 | Regents of the University of California | Methods for the cyto-protection of the trabecular meshwork |
| 5674888, | Jun 07 1995 | Regents of the University of California | Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division |
| 5889033, | Feb 14 1991 | Mount Sinai School of Medicine | Method and composition for the treatment of apathy-amotivation syndrome |
| 6926907, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 7115618, | Aug 25 1992 | G.D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| 7320983, | Aug 25 1992 | G.D. Searle LLC | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| 7736666, | Mar 08 2000 | Nicox Science Ireland | Self emulsifying drug delivery system |
| 7815933, | Sep 07 2001 | NICOX S A | Self emulsifying drug delivery system |
| 8067033, | Nov 30 2007 | HORIZON MEDICINES LLC | Stable compositions of famotidine and ibuprofen |
| 8067451, | Jul 18 2006 | HORIZON THERAPEUTICS USA, INC | Methods and medicaments for administration of ibuprofen |
| 8206741, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 8211430, | Mar 04 2005 | CureDM Group Holdings, LLC | Methods and pharmaceutical compositions for treating type 1 diabetes mellitus and other conditions |
| 8309127, | Nov 30 2007 | HORIZON MEDICINES LLC | Stable compositions of famotidine and ibuprofen |
| 8318202, | Nov 30 2007 | HORIZON MEDICINES LLC | Stable compositions of famotidine and ibuprofen |
| 8383578, | May 25 2005 | CureDM Group Holdings, LLC | Peptides, derivatives and analogs thereof, and methods of using same |
| 8449910, | Nov 30 2007 | HORIZON MEDICINES LLC | Stable compositions of famotidine and ibuprofen |
| 8501228, | Nov 30 2007 | HORIZON MEDICINES LLC | Stable compositions of famotidine and ibuprofen |
| 8557285, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 8771643, | Jan 04 2008 | SCHACHTEL RESEARCH COMPANY, INC ; Schabar Research Associates LLC | Use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound |
| 8816047, | Aug 30 2007 | CureDM Group Holdings, LLC | Compositions and methods of using proislet peptides and analogs thereof |
| 8829158, | May 25 2005 | CureDM Group Holdings, LLC | Peptides, derivatives and analogs thereof, and methods of using same |
| 8852636, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 8858996, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDS |
| 8865190, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 8945621, | Jun 25 2009 | HORIZON THERAPEUTICS USA, INC | Method for treating a patient at risk for developing an NSAID-associated ulcer |
| 9044465, | Jan 04 2008 | SCHABAR RESEARCH ASSOCIATES, LLC | Use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound |
| 9161920, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 9198888, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 9220698, | Sep 09 2008 | HORIZON THERAPEUTICS USA, INC | Method for delivering a pharmaceutical composition to patient in need thereof |
| 9345695, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 9364439, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 9393208, | Sep 09 2008 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Method for delivering a pharmaceutical composition to patient in need thereof |
| 9539214, | Dec 28 2011 | GENUS LIFESCIENCES, INC | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
| 9707181, | Jun 01 2001 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| 9801824, | Sep 09 2008 | NUVO PHARMACEUTICALS IRELAND DESIGNATED ACTIVITY COMPANY | Method for delivering a pharmaceutical composition to patient in need thereof |
| 9987231, | Dec 28 2011 | GENUS LIFESCIENCES, INC | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
| RE42889, | Aug 25 1992 | G.D. Searle LLC | α- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| RE43596, | Aug 25 1992 | G.D. Searle LLC | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| RE43802, | Aug 25 1992 | G.D. Searle LLC | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| Patent | Priority | Assignee | Title |
| 4401665, | Apr 14 1981 | Bristol-Myers Company | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use |
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